Complete pathological response in patients with bladder cancer: predictors and outcomes

Abstract

Pathologic complete response (pCR) in bladder cancer, most often defined as pT0N0 at radical cystectomy (RC) following transurethral resection of the bladder tumor with/without neoadjuvant therapy, has emerged as a powerful prognostic marker. Predicting pCR before RC and understanding its prognostic nuances are increasingly important as perioperative chemotherapy and immunotherapy evolve. In this study, we reviewed the contemporary evidence regarding definitions and clinical contexts of pCR in bladder cancer; clinical, pathological, imaging, molecular, and liquid-biopsy predictors of pCR; and outcomes and recurrence patterns in patients achieving pCR. We found out that pCR rates vary widely according to treatment regimen, patient selection, and underlying tumor biology, ranging from 5%–15% after transurethral resection alone, 25%–35% with cisplatin-based chemotherapy, and up to 40% with combination chemoimmunotherapy. However, regardless of upfront treatment modality, pCR correlates with significantly improved overall survival and recurrence-free survival. A growing body of evidence has identified predictors of pCR spanning clinical and histopathologic features, molecular and genomic alterations, particularly DNA damage response gene mutations, immune biomarkers (e.g., tumor mutational burden and immune gene expression signatures), advanced imaging with multiparametric magnetic resonance imaging and vesical imaging reporting and data system–based assessment, and circulating tumor DNA dynamics. Among these, circulating tumor DNA clearance during neoadjuvant therapy has demonstrated particularly strong predictive and prognostic value. Despite the favorable outcomes associated with pCR, recurrence risk is not negligible, especially among ypT0 patients, highlighting the importance of risk-adapted postoperative surveillance. In parallel, bladder-preserving strategies for carefully selected patients achieving a clinical complete response remain investigational, limited by imperfect concordance between clinical and pathologic response and requiring rigorous multimodal assessment and close follow-up. Collectively, contemporary data indicate that no single biomarker is sufficient to reliably predict pCR; rather, integrated multimodal models offer the greatest potential to refine neoadjuvant treatment selection, inform bladder preservation, and individualize surveillance while maintaining oncologic safety.

Keywords

muscle-invasive bladder cancer neoadjuvant therapy pathologic complete response surveillance tumor biomarkers

Introduction

Bladder cancer remains a significant global health burden, with over 84,000 new cases expected in the United States in 2025, making it one of the most common malignancies in both men and women.¹ For patients with non-metastatic muscle-invasive bladder cancer (MIBC), radical cystectomy (RC) with bilateral pelvic lymphadenectomy is the cornerstone of curative-intent treatment. Contemporary guidelines emphasize the integration of platinum-based neoadjuvant chemotherapy (NAC) prior to surgery, citing increased rates of pathological complete response (pCR) and improvements in long-term survival compared to surgery alone.^2,3 Across tumor types, pCR is widely regarded as a favorable surrogate for long-term oncologic outcomes, and bladder cancer is no exception. In this context, pCR, defined as ypT0N0 or pT0N0 at the time of RC following NAC and/or transurethral resection of the bladder tumor (TURBT), has emerged as a robust prognostic marker.

NAC has been particularly impactful in downstaging disease, with level I evidence confirming its role in response rates and improving survival following RC.^4,5 More recent multi-institutional data have highlighted chemotherapy regimen-specific differences in achieving higher pCR.⁶ Building upon this foundation, perioperative systemic therapy has expanded to incorporate immunotherapy. The phase III NIAGARA trial demonstrated an improvement in pCR and a survival advantage for durvalumab plus platinum-based chemotherapy prior to cystectomy, followed by adjuvant durvalumab, leading to its regulatory approval in 2025.⁷ Collectively, these findings underscore pCR, particularly in the neoadjuvant setting, as a critical therapeutic endpoint in MIBC.

Despite the clear prognostic significance of pCR, several important clinical questions remain. First, which patients are most likely to achieve pCR following different neoadjuvant strategies (chemotherapy vs immunotherapy), and how do outcomes differ between pCR achieved after systemic therapy (ypT0) versus pT0 status following TURBT alone? Second, how accurately can pCR be predicted preoperatively using clinical characteristics, imaging modalities, tumor genomics, or liquid-biopsy approaches? Third, what are the patterns of recurrence and long-term survival outcomes among patients achieving pCR, and do these differ based on whether pCR is attained with or without NAC? Finally, can carefully selected patients with a clinical complete response safely undergo bladder-preserving strategies? In this narrative review, we address these questions by synthesizing contemporary evidence on the definitions, predictors, and outcomes of pCR, while highlighting practical surveillance considerations and future directions.

Methods

In this narrative review, we conducted a targeted literature search of PubMed/MEDLINE, as well as relevant medical society meetings through December 2025, focusing on studies of MIBC managed by RC with or without NAC. Eligible studies were those evaluating incidence, predictors, and oncologic outcomes of pCR at the time of cystectomy. Articles were screened for relevance by the authors in a stepwise fashion, beginning with title review, followed by abstract assessment, and subsequently full-text evaluation (if available). Study designs included randomized controlled trials, prospective multicenter comparative studies, non-randomized case series, meta-analyses, narrative literature reviews, and relevant meeting abstracts. Studies involving non-human models and non-English publications, as well as case reports, commentaries, and editorials, were excluded. This review was conducted in accordance with narrative review guidelines outlined by the Journal of Graduate Medical Education.⁸

Results

Definitions and clinical context of pCR

The U.S. National Cancer Institute defines pCR as the absence of all detectable cancer in surgical or biopsy specimens following therapy. In bladder cancer, pCR is typically defined as ypT0N0 after NAC followed by RC, and as pT0N0 when RC is performed without prior systemic therapy (i.e., following TURBT alone).^9–11 These definitions form the basis of outcome analyses and clinical trial endpoints and should be applied consistently to avoid conflating distinct clinical contexts.

It is important to distinguish between pCR and clinical complete response (cCR). cCR is assessed using cystoscopy, imaging, and biopsies, and does not reliably predict pCR at the time of RC. Rates of discordance vary according to histologic subtype and imaging modality. For instance, plasmacytoid and micropapillary variants exhibit higher discrepancies between imaging-based cCR and final pathologic findings. These observations underscore the need for pathologic confirmation when RC is planned and for rigorous surveillance strategies when bladder preservation is pursued.^11,12 Contemporary evidence emphasizes that, although cCR is a valuable complementary endpoint, it cannot yet replace pCR in clinical decision-making outside of structured protocols or clinical trials.^10,11

Rates of pCR

pCR rates at RC vary substantially by treatment approach, that is, no neoadjuvant therapy (TURBT alone), with NAC, and with neoadjuvant chemoimmunotherapy. Among patients receiving upfront systemic therapy, both the type of regimen and the number of treatment cycles influence pCR rates.

pCR following TURBT alone

pCR at RC in patients who have not received neoadjuvant systemic therapy, essentially reflecting complete tumor eradication by TURBT, is less common but well documented. Large institutional series report pT0N0 rates ranging from 5% to 15% among cystectomy specimens performed without NAC, with most estimates clustering near 10%.^13,14 Factors associated with pT0 include thorough TURBT technique, absence of lymphovascular invasion, and lower initial clinical stage.^15–17 Despite a favorable prognosis compared to higher-stage cohorts, recurrence can still occur, particularly in those with variant histologies, underscoring the need for continued surveillance even in this seemingly “low-risk” group.¹³

pCR following NAC

Cisplatin-based NAC prior to RC remains the standard for eligible MIBC patients and improves survival over RC alone.¹⁸ The pCR rates in this setting has been reported as high as 22%–42%, with most contemporary studies reporting rates between 26% and 31% (Table 1).^19,20 A meta-analysis of 15 trials including 1535 patients found a pooled pCR rate of 30.91%.²¹ Real-world data from patients receiving NAC followed by RC showed 29% achieving pCR.²⁰ The incidence of pCR following NAC is influenced by patient selection, regimen intensity, and staging accuracy.^6,9

Table 1.

Summary of selected landmark and contemporary studies reporting pathologic complete response following neoadjuvant systemic therapy for muscle-invasive bladder cancer.

Study^Ref	Study type	Neoadjuvant regimen	Population	Number	pCR rate
SWOG 8710⁴	Phase III RCT	MVAC × 3	cT2–T4a MIBC	317	38% (MVAC) vs 15% (RC alone)
VESPER²²	Phase III RCT	dd-MVAC vs GC	MIBC	437	42% (dd-MVAC) vs 36% (GC)
Petrelli et al.⁹	Meta-analysis (13 trials)	Cisplatin-based NAC (various)	MIBC	886	28.6% (pooled)
ABACUS²⁸	Single-arm phase II trial	Atezolizumab × 2	Cisplatin-ineligible cT2–T4a MIBC	95	31% (defined as pT0/Tis)
PURE-01²⁶	Single-arm phase II trial	Pembrolizumab × 3	cT2–4a MIBC (Cisplatin eligible and ineligible)	114	42% (in high PD-L1 expression 54%)
NIAGARA⁷	Phase III RCT	Durvalumab + GC vs GC alone	Cisplatin-eligible MIBC	1063	37.3% (Durvalumab + GC) vs 27.5% (GC alone)
Ayaz et al.²¹	Meta-analysis (28 trials)	NAC, NAI, or NACI (various)	MIBC	2138	30.91% (NAC), 30.92% (NAI), 42.25% (NACI)
EV-303³⁰	Phase III RCT	EV + Pembrolizumab	Cisplatin-ineligible MIBC	344	57.1% vs 8.6% (RC alone)
EV-304³¹	Phase III RCT	EV + Pembrolizumab vs GC	Cisplatin-eligible MIBC	806	55.8% vs 32.5%

EV, enfortumab vedotin; GC, gemcitabine–cisplatin; MIBC, muscle-invasive bladder cancer; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; NAC, neoadjuvant chemotherapy; NACI, neoadjuvant chemoimmunotherapy; NAI, neoadjuvant immunotherapy; pCR, pathological complete response; RCT, randomized clinical trial.

The pCR rates may differ among different NAC regimens. The French phase III VESPER trial compared six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) to four cycles of gemcitabine–cisplatin (GC) given in the neoadjuvant or adjuvant settings in non-metastatic MIBC. In the neoadjuvant subset, dd-MVAC improved 3-year progression-free survival and yielded a greater proportion of organ-confined responses (<ypT3N0). pCR (ypT0N0) was numerically higher with dd-MVAC (42% vs 36%) but not statistically different.²² However, another study showed that dd-MVAC achieved approximately twice the pCR rate compared to GC. In this study of 1113 patients who underwent RC, adjusted analysis comparing dd-MVAC with GC demonstrated a higher likelihood of downstaging and pCR with dd-MVAC (odds ratio (OR): 1.84 and 2.67, respectively). Similar results were achieved after propensity score matching (OR 1.52; 95% CI: 0.99–2.35).⁶ A meta-analysis of five retrospective studies did favor MVAC for complete response rate (OR: 1.57), supporting this regimen as a preferred option when tolerated.²³

The number of cycles is also important to consider in this context. A multi-center retrospective study comparing three versus four cycles of cisplatin-based NAC to non-standard of care NAC (1–2 cycles or non-cisplatin-based regimens) in non-metastatic MIBC patients found no difference in yPT0 rates among those undergoing three versus four cycles of standard of care NAC, but did find higher rates compared to non-standard of care chemotherapy regimens (p = 0.03). Additionally, the authors noted ypT0 patients (n = 86) had improved 3-year overall survival (85.3% vs 67.1%, p = 0.01) and 3-year recurrence-free survival rates (88% vs 64%, p < 0.01) when compared to >ypT0 patients (n = 232).²⁴ A recent study demonstrated that patients who received at least four cycles (vs ⩽3 cycles) of accelerated MVAC had a significantly higher likelihood of achieving a partial or complete response. Moreover, receiving ⩾5 cycles compared with four cycles was associated with a significantly higher rate of pCR (63.2% vs 33.8%, p = 0.02).²⁵ A systematic review of three studies, with 1091 patients, comparing three versus four cycles of GC found higher pCR and pathologic downstaging with four cycles, with similar survival and recurrence rates. These data suggest that, when feasible, completing four cycles may optimize pCR probability without clear survival trade-offs, though timely surgery and patient tolerance remain important.²⁶

pCR following neoadjuvant immunotherapy and chemoimmunotherapy

Neoadjuvant immunotherapy alone (checkpoint inhibitor monotherapy) produces pCR rates of 31%–37% in most studies, with a meta-analysis showing a pooled rate of 30.92% (Table 1).²¹ Single-agent pembrolizumab achieved a 42% pCR rate in the PURE-01 study.²⁷ In cisplatin-ineligible matched cohorts, neoadjuvant pembrolizumab was associated with higher pT0 rates and improved survival compared with immediate cystectomy, although these findings warrant cautious interpretation given the non-randomized design.²⁸ The response rates following other immunotherapy agents, such as atezolizumab, have also been studied. In the phase II ABACUS trial, two cycles of atezolizumab prior to RC demonstrated meaningful pCR rates in urothelial carcinoma and variant histologies, with exploratory biomarker work (including ctDNA) correlating with response and disease-free survival. Interim reports and conference presentations show feasibility and safety; final randomized data are awaited to define comparative efficacy against chemotherapy.²⁹

Neoadjuvant chemoimmunotherapy demonstrates the highest pCR rates at 33%–42%.^19,21 The landmark NIAGARA trial showed perioperative durvalumab plus GC achieved a 33.8% pCR rate (re-analysis: 37.3%) compared to 25.8% with chemotherapy alone.⁷ A meta-analysis of eight trials with 315 patients found a pooled pCR rate of 42.25% with chemoimmunotherapy, significantly higher than chemotherapy or immunotherapy alone.²¹

Neoadjuvant therapy with enfortumab vedotin plus pembrolizumab has recently shown substantial efficacy in patients with bladder cancer undergoing RC. In the phase III EV-303 trial, this regimen was evaluated in cisplatin-ineligible patients and compared with surgery alone. At 2 years, estimated event-free survival was 74.7% in the treatment arm versus 39.4% in the control arm (p < 0.001), while overall survival was 79.7% versus 63.1% (p < 0.001), respectively. pCR rates were also significantly higher with the combination therapy (57.1% vs 8.6%; p < 0.001).³⁰ More recently, findings from the phase III EV-304 trial, presented at ASCO GU 2026, demonstrated that perioperative enfortumab vedotin plus pembrolizumab significantly improved event-free survival, overall survival, and pCR compared with standard neoadjuvant gemcitabine–cisplatin, achieving pCR rates of approximately 55.8% versus 32.5%, respectively.³¹

Predictors of pCR

Multiple clinical, molecular, imaging, and biomarker features may predict pCR in bladder cancer patients undergoing RC with or without NAC.

Clinical and pathologic characteristics

Traditional clinical variables, such as age, sex, hydronephrosis, baseline T stage, and clinical node status, have limited standalone predictive accuracy for pCR.³² Tumor stage at diagnosis (clinical T stage) might be the most important variable, where a higher stage often correlates with a lower likelihood of pCR. A meta-analysis, including a total of 30,293 patients, demonstrated that NAC was associated with higher rates of pCR at RC, although pCR rates decreased with increasing clinical T stage. Among patients with cT3–4 disease, pCR was achieved in 23.9% of those treated with TURBT plus NAC compared with 3.8% treated with TURBT alone (p < 0.001). Similarly, in patients with cT2 disease, pCR rates were 34.3% with TURBT plus NAC versus 20.2% with TURBT alone (p = 0.007).³³ Nevertheless, clinical staging alone is a poor standalone predictor and has limited discriminatory power.³⁴

Patients with pure urothelial carcinoma are more likely to achieve pCR compared with those having variant histology. Pokuri et al.³⁵ examined 50 post-NAC cystectomy specimens for MIBC patients and found pure urothelial histology to be the only predictor of pCR (OR: 0.09). Variant histology subtypes often display more aggressive biology and lower pCR rates. A pathological perspective study correlating pre-chemotherapy TURBT findings and post-chemotherapy magnetic resonance imaging (MRI) with RC pathology found that plasmacytoid cases demonstrated the largest discordance between MRI and surgical pathology and that plasmacytoid, micropapillary, and squamous differentiation did not show pCR.³⁶ Similarly, a single-center retrospective series comparing nine patients with urothelial carcinoma with squamous differentiation to 29 with pure urothelial carcinoma who underwent NAC followed by RC for T1-4, N0-2 MIBC found a pCR rate for those with squamous differentiation of 0%, with 34.5% in the pure urothelial group (p = 0.04).³⁷ These data support heightened caution in interpreting cCR for variant histologies and suggest that standard pCR predictors may be less informative in these subtypes.

The quality and completeness of TURBT are also important in this context. High-quality TURBT remains essential for staging accuracy, margin assessment, and early eradication of visible disease, particularly in trimodal therapy approaches. International consensus emphasizes standardized technique (including detrusor muscle sampling), re-TURBT in selected cases, and enhanced cystoscopic techniques (when available) to reduce understaging and optimize outcomes.^15,38,39 Small institutional series linking thorough TURBT, surgeon experience, standardized technique, and absence of lymphovascular invasion to pT0 findings at RC suggest a potential contribution to pCR in non-NAC contexts, though broader validation is required.⁴⁰

Molecular and genomic features

Tumor mutational burden (TMB) is an important and reliable DNA biomarker for neoadjuvant immunotherapy response. In the PURE-01 study, higher mean TMB was significantly associated with pCR versus non-responders, with a 10 mutations/Mb cutoff helping identify predicted non-responders.⁴¹ The relationship between TMB and PD-L1 expression is complex. For patients with high TMB (>11 mut/Mb), pCR probability was significantly associated with higher PD-L1 combined positive score (CPS) (p = 0.004), while this association was absent in low TMB patients. In addition, composite biomarker models combining TMB, PD-L1 CPS, and clinical T stage have been shown to improve prediction.⁴²

DNA damage response (DDR) gene mutations also predict chemotherapy response. Mechanistically, tumors with defective DDR may be more susceptible to platinum-induced DNA damage. In a study of 105 pre-NAC tumor specimens from the SWOG S1314 trial, mutations in ATM, RB1, FANCC, or ERCC2 predicted pCR (OR: 5.36), with particularly high negative predictive value (86%).⁴³ Among DDR genes, ERCC2 helicase-domain mutations are consistently associated with cisplatin sensitivity and pCR after cisplatin-based NAC. A 2025 large multinational cohort using quantitative functional profiling demonstrated that heterozygous helicase-domain ERCC2 missense variants markedly sensitize tumors to cisplatin and correlate with improved neoadjuvant responses.^44,45 Earlier studies found ERCC2 mutations enriched among pCR “responders” and proved mechanistically that ERCC2 helicase mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in preclinical bladder cancer models.⁴⁶ While mutation frequencies are modest (~7%–12%), ERCC2 remains among the most compelling predictive biomarkers for platinum-based NAC.⁴⁶

Immune gene expression signatures predict immunotherapy response. The ABACUS trial, evaluating neoadjuvant atezolizumab, found a high presence of intraepithelial CD8+ cells to be significantly associated with pCR when compared to the absence of CD8 (4% vs 20%).⁴⁷ In addition, higher baseline stromal CD8+ expression correlated with improved relapse-free survival (hazard ratio (HR): 0.25).⁴⁸ The PURE-01 study evaluating neoadjuvant pembrolizumab found the Immumo190 signature to be associated with pCR (p = 0.02). This association remained significant after multivariable analysis.⁴⁹ In the setting of chemoimmunotherapy, higher pre-treatment tumor PD-L1 and TIGIT RNA expression were associated with complete response.⁵⁰

Molecular subtyping (e.g., basal/luminal) has also been linked to differences in presentation and outcomes as well as the likelihood of achieving pCR at RC. Across classification systems, basal tumors, characterized by high proliferative activity and an immune-inflamed microenvironment, consistently demonstrate higher pCR rates and greater benefit from cisplatin-based NAC, despite worse baseline prognosis, supporting a predictive rather than purely prognostic role. In contrast, luminal tumors, particularly the luminal-papillary subtype often enriched for FGFR3 alterations, are associated with lower pCR rates to chemotherapy, although subsets with DDR alterations or high TMB may still respond. In neoadjuvant immunotherapy cohorts, the association between basal–luminal status and pCR is less consistent, with immune-related biomarkers frequently outperforming molecular subtype alone. Overall, while molecular subtyping is not sufficient as an individual predictor, it contributes meaningful biologic context and is most informative when integrated with genomic, immune, and circulating biomarkers in multimodal predictive models.^51–54

Imaging and radiomics

Standard computed tomography (CT) or MRI response assessments after NAC show suboptimal accuracy in predicting pCR.³⁴ Radiomics features extracted from baseline CT images (e.g., texture, shape, intensity metrics) have been shown to predict pCR when combined with clinical stage and tumor size. In one study, the radiomics signature showed good performance for predicting pCR in both the training (AUC 0.85) and validation (AUC 0.75) sets.⁵⁵

Multiparametric MRI (mpMRI) with vesical imaging reporting and data system (VI-RADS) scoring has shown promise for response assessment post-NAC. Retrospective analyses report that radiologic complete response via nacVI-RADS or simplified 3-step scores correlates with pCR with high specificity (96%) but low sensitivity (36%).⁵⁶ Educational and review resources emphasize standardized acquisition (T2-Weighted Imaging: T2WI, Diffusion-Weighted Imaging: DWI, Dynamic Contrast-Enhanced: DCE), timing relative to TURBT, and pitfalls (e.g., post-resection reactive changes), while new work explores thresholds and quantitative features (tumor contact length, maximum diameter) to improve prediction.^57,58 In clinical practice, mpMRI complements, but does not replace, pathologic assessment and should inform surveillance protocols when bladder preservation is considered.

Circulating tumor DNA

ctDNA status at multiple timepoints is highly prognostic and predictive. At baseline, ctDNA positivity was detected in up to 63% of patients and predicted lower pCR rates.^59,60 Furthermore, ctDNA clearance after neoadjuvant therapy demonstrated high sensitivity (98%) for predicting pCR, though specificity was limited (53%). The absence of ctDNA clearance identifies patients unlikely to achieve pCR with a high negative predictive value.⁶¹ ctDNA dynamics during treatment independently predicted outcomes when adjusted for pathologic downstaging (HR 4.7; p = 0.03).⁶² In the post-cystectomy, ctDNA positivity was also highly prognostic, with ctDNA-positive patients showing significantly worse recurrence-free survival and overall survival.⁶⁰ Notably, no relapses were observed in patients who were ctDNA-negative at baseline and after neoadjuvant therapy.⁴⁸ Moreover, ctDNA-guided analyses from IMvigor010 and prospective IMvigor011 show that ctDNA-positive patients derive significant benefit from atezolizumab, whereas ctDNA-negative patients can be safely surveilled, supporting personalization of adjuvant therapy and surveillance intensity.^45,63

Urinary tumor DNA (utDNA) offers an alternative non-invasive approach. Prior studies have shown that utDNA is detectable in 89% of urine supernatants pre-treatment, with higher detection rates than plasma (43%). utDNA minimal residual disease detection prior to cystectomy correlated significantly with pathologic response (81% sensitivity and specificity) and progression-free survival (HR 7.4; p = 0.02).^59,64,65

Outcomes of patients achieving pCR

Patients with MIBC who achieve pCR at RC have excellent long-term outcomes, with 5-year overall survival of 86%–92% and 5-year recurrence-free survival of 84%–93%.^9,66,67 This represents a 55% lower risk of death and 81% lower risk of recurrence compared to patients with residual disease.⁹ A meta-analysis of 13 trials (n = 886) showed that pCR after NAC and RC is strongly associated with improved overall survival (relative risk (RR): 0.45) and recurrence-free survival (RR: 0.19).⁹ Pathology-based series of ypT0N0 RC specimens document characteristic post-treatment changes (scar, foreign body reaction, dystrophic calcification) and outstanding survival, with 5-year recurrence-free survival of 94% and overall survival of 89%, and no cancer-specific deaths, emphasizing that true ypT0N0 portends an excellent prognosis.⁶⁸

The outcomes of pT0 versus ypT0 may be different. Recent multicenter analyses suggest that pT0 patients who received NAC may have improved cancer-specific and recurrence-free survival compared to pT0 patients without NAC, while overall survival differences vary and can be attenuated on multivariable analyses accounting for sex, clinical stage, and nodal status.^69,70 On the other hand, a large multicenter study found no statistically significant difference in overall survival between these groups, with mean survival estimates of 186.7 months for pT0 versus 138 months for pTa/Tis/T1 (p = 0.58).⁶⁷ Both groups demonstrated substantially better outcomes than patients with residual muscle-invasive disease. These nuances likely reflect baseline disease burden, biology, and selection rather than an intrinsic disadvantage of one pathway to pT0.

Recurrence patterns in pT0N0 patients are also worth exploring. Large academic cohorts have clarified recurrence risk and timing among these patients. In a 20-year experience including 2222 RC patients, of whom 234 had pT0N0, overall recurrence was uncommon (6.8%) but occurred more frequently in ypT0 than in pT0 patients, typically within the first 2 years. Variant histology was associated with a higher recurrence risk (12.2% vs 5.4% for pure urothelial carcinoma, p = 0.02); nevertheless, achieving pCR remained strongly prognostic for excellent outcomes regardless of baseline histology.¹³ Importantly, no patients with clinical Ta/Tis disease who achieved pT0 experienced recurrence after RC. The excellent outcomes in pCR patients support the value of neoadjuvant therapy in achieving pCR, though long-term surveillance remains essential as recurrences can develop up to 4 years or more after surgery.¹³

Bladder preservation in clinical complete responders: Evidence and caution

For patients achieving cCR after NAC, bladder preservation through stringent surveillance and selective consolidation has long been debated. Classic experiences and modern reviews indicate that some cCR patients can be managed without immediate RC, but accurate identification is challenging due to imperfect concordance between cCR and pCR, particularly in variant histologies.¹² In a multicenter study of 148 patients with MIBC who elected surveillance following a cCR to TURBT and NAC, active surveillance yields 5-year disease-specific survival of 90% and overall survival of 86%, with 76% maintaining bladder-intact status. However, 48% experience bladder recurrence, including 11% with muscle-invasive disease and 37% with non-invasive disease. Importantly, salvage cystectomy prevents cancer-specific death in 75% of patients with muscle-invasive relapse and 93% with non-invasive relapse.⁷¹ Another long-term study with 15-year follow-up showed approximately 40% of patients remain alive with intact bladders, 40% die from other causes, 10% require cystectomy, and 10% die from bladder cancer. One-third experience local recurrence, with risk persisting beyond 10 years, necessitating lifelong surveillance.⁷²

Neoadjuvant immunotherapy alone or combined with chemotherapy demonstrates superior bladder preservation outcomes compared to NAC-driven approaches. In a multicenter propensity-matched analysis, neoadjuvant immunotherapy-driven bladder preservation achieved 2-year bladder-intact disease-free survival of 90.28% versus 71.59% with NAC (HR: 2.32, p = 0.021). Outcomes were comparable to traditional trimodal therapy, with 2-year bladder-intact disease-free survival of 86.42% versus 80.89%.⁷³ A study of pembrolizumab or chemotherapy followed by bladder preservation in patients declining definitive therapy showed 52.1% cCR rate with pembrolizumab versus 36.7% with chemotherapy (p = 0.26). Patients achieving cCR demonstrated significantly prolonged progression-free survival (median not reached vs 10.2 months, p < 0.001) and overall survival (median not reached vs 24.4 months, p = 0.004).⁷⁴

Taken together, bladder preservation may be reasonable in carefully selected cCR patients within structured protocols, incorporating multi-modal assessment (cystoscopy/biopsy, mpMRI/VI-RADS, and ctDNA) and rapid salvage strategies for relapse. Until validated, routine non-trial bladder preservation in cCR should be pursued cautiously.

Surveillance after pCR: Practical considerations

Given the low but non-zero recurrence risk after pT0N0 RC, especially within 24 months for ypT0, surveillance is necessary but should be risk-adapted. Importantly, recurrence patterns and risk may differ between patients with de novo pT0 disease and those downstaged to pT0 following NAC (ypT0), necessitating nuanced surveillance approaches (Table 2).

Table 2.

Surveillance recommendations after pathologic complete response at radical cystectomy.

Domain	Modality	Timing	Risk-adapted considerations
Clinical evaluation	History and physical examination	At routine follow-up visits	Applies equally to pT0 and ypT0
Lab tests	Renal function, metabolic panels	Periodic, per diversion type, and comorbidities	Applies equally to pT0 and ypT0
Urine tests	Urine cytology	Every 6–12 months during years 1–2; annually thereafter if indicated	Consider more strongly in patients with adverse preoperative features (e.g., CIS, multifocal disease), independent of pT0 vs ypT0 status
	Urethral wash cytology	As clinically indicated	Primarily for high-risk patients (positive urethral margin, multifocal CIS, prostatic urethral involvement)
Imaging	CT or MRI abdomen/pelvis ± chest imaging	Every 6–12 months for years 1–2; annually up to 5 years	Closer surveillance may be warranted in ypT0 patients, particularly those with higher clinical stage prior to NAC
Molecular tests	Tumor-informed circulating tumor DNA (ctDNA)	Serial assessment (timing investigational)	Particularly useful in ypT0 patients to identify occult residual risk

CIS, carcinoma in situ; CT, computed tomography; MRI, magnetic resonance imaging; NAC, neoadjuvant chemotherapy.

Imaging: Cross-sectional imaging remains the cornerstone of post-RC surveillance, even among patients with pCR. Current guideline-based strategies recommend CT or MRI of the abdomen and pelvis, with or without chest imaging, every 6–12 months for the first 2 years following cystectomy, and annually thereafter up to 5 years.^2,3 However, closer follow-ups in the first 2 years may be needed in ypT0 patients compared to the pT0 group, particularly among those with higher clinical stage before NAC.¹³ It is important to note that no single surveillance strategy is appropriate for all patients; follow-up should be individualized based on tumor biology, sites of disease, and time from treatment. Additionally, reassessment should be prompted by any new or worsening symptoms (e.g., hematuria, weight loss, pain, or respiratory symptoms), irrespective of scheduled imaging intervals.

Urine tests: The role of urine cytology following RC in patients with pCR is limited but may be considered every 6–12 months during years 1–2 and then annually if clinically indicated, particularly among those with adverse preoperative features, such as carcinoma in situ (CIS) or multifocal disease. Despite its low sensitivity, urine cytology may aid in identifying upper tract recurrence. Urethral wash cytology may also be considered for high-risk disease (positive urethral margin, multifocal CIS, prostatic urethral invasion).^2,3

ctDNA monitoring: Although not routinely recommended by current guidelines, tumor-informed ctDNA assays can detect molecular recurrence earlier than imaging and stratify adjuvant immunotherapy benefit. Serial ctDNA negativity supports de-escalation of surveillance intensity, while ctDNA positivity warrants closer follow-up and therapeutic consideration.^75,76 In patients achieving pCR, ctDNA may provide biologic risk stratification beyond conventional staging, potentially identifying a subset of patients who remain at risk for occult disease despite complete pathological response. These measures accommodate the earlier recurrence tendency observed in ypT0 subsets and harness ctDNA’s ability to personalize surveillance. While ctDNA-guided surveillance and intervention strategies are under active investigation, their integration into routine clinical practice remains investigational and should currently be considered within clinical trials or prospective registries.

Clinical assessment and laboratory evaluation: Routine clinical evaluation, including history and physical examination, remains an essential component of surveillance to assess for symptoms suggestive of recurrence, complications related to urinary diversion, and long-term treatment-related morbidity. Laboratory testing, including renal function and metabolic assessment, is particularly relevant in patients with urinary diversion but does not directly contribute to oncologic surveillance for recurrence in pCR patients.

Future directions

Moving beyond single markers, composite panels integrating DDR signatures, molecular subtypes, TMB/PD-L1 CPS, radiomics (VI-RADS-derived), and ctDNA dynamics may better predict pCR and tailor neoadjuvant choices (chemotherapy, immunotherapy, or combination approaches). In parallel, harmonization of mpMRI protocols and validation of VI-RADS adaptations for post-NAC settings (nacVI-RADS) will be key to improving noninvasive response assessment and integrating imaging with endoscopic and biopsy-based evaluation.^56,57 Furthermore, randomized data now support ctDNA-guided adjuvant immunotherapy; extending this paradigm to neoadjuvant treatment selection and bladder-preserving pathways may allow refinement of treatment intensity and timing, as well as surveillance de-escalation in patients with serially negative ctDNA.⁷⁵ Finally, although level I evidence supports the use of NAC before RC, emerging immunotherapeutic agents and combination strategies, including immune checkpoint inhibitors with or without antibody–drug conjugates or chemotherapy, remain active areas of investigation, with substantial potential for biomarker-enriched, individualized treatment approaches.^77,78

Conclusion

pCR remains a highly favorable oncologic state in bladder cancer and is consistently associated with excellent long-term outcomes. However, both the achievement and interpretation of pCR require careful contextualization, as pCR rates vary according to treatment regimen, patient selection, and underlying tumor biology. Predictive factors encompass a broad spectrum, including clinical and histopathologic characteristics, DDR–related genomic alterations, multiparametric MRI with VI-RADS–based assessment, and ctDNA dynamics. No single biomarker is sufficient to reliably predict pCR; rather, integrated multimodal models offer the greatest potential to optimize patient selection for neoadjuvant therapy, inform bladder-preserving strategies in patients achieving clinical complete response, and individualize postoperative surveillance. As ctDNA-guided approaches continue to mature, imaging protocols become standardized, and biomarker-enriched perioperative trials report their outcomes, clinicians will be increasingly equipped to tailor treatment intensity, expand bladder preservation to appropriately selected patients, and maintain oncologic safety.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Alireza Ghoreifi

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